Prevention and treatment of diastolic flow reversal

ABSTRACT

Methods and devices are described for preventing diastolic flow reversal and/or reducing peripheral vascular resistance in a patient. Also described are methods of cosmetic treatment, and methods of promoting delivery of therapeutic agents or contrast agents to bones and related tissues.

This application is a continuation of application Ser. No. 14/677,295,filed Apr. 2, 2015, which is a divisional of application Ser. No.13/138,268, filed Nov. 4, 2011, now U.S. Pat. No. 9,707,387, which isthe national stage application of PCT Application No. PCT/GB2009/051713,filed Dec. 15, 2009, which claims priority based on United KingdomApplication No. 0823213.4, filed Dec. 19, 2008, the contents of whichare incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a method and device for medical and/orcosmetic treatment. In particular, one aspect of the invention relatesto a method for reducing peripheral vascular resistance in the bloodcirculation of a patient; other aspects of the invention relate tomethods of treatment of disorders characterised by increased peripheralvascular resistance. The invention also relates to a device forimplementing the method. Further aspects of the invention relate toother uses of the device.

BACKGROUND OF THE INVENTION

A method and device for reduction or treatment of deep vein thrombosis(DVT) are described in international patent application WO2006/054118.This device includes electrodes which are secured to the leg of apatient and used to provide electrical stimulation to the muscles.Preferably the electrodes are arranged to stimulate the lateral and/ormedial popliteal nerves, which causes the calf muscles to contract. Thisin turn activates the calf musculovenous pump, in which bloodcirculation is promoted by muscle contraction, so serving to reduce therisk of thrombosis in the limb. Other musculovenous pumps include thefoot pump, and the device may be used to stimulate this as well as, orinstead of, the calf pump. The device is preferably used to induceisometric contraction of the muscles, such that the musculovenous pumpsmay be activated but limb movement from the stimulation is reduced oravoided.

As described in WO2006/054118, use of the device in the manner describedhas been demonstrated to increase venous emptying in the leg, as well asto increase cortical blood flow in the long bones of the leg. Due tothese effects, the device is suggested for use to treat conditions otherthan DVT characterised by impaired venous blood flow, including ulcers,varicose veins, ischaemia, oedema, phlebitis, osteoporosis, peripheralvascular disease, coronary heart disease, and hypertension. Thesedisorders are considered to be treatable on the basis that the deviceand method can increase venous blood flow.

We have now surprisingly determined that the device, and similardevices, may be used to alter the patterns of blood flow in a patient.

SUMMARY OF THE INVENTION

We present here evidence that electrical stimulation of muscles may beused not only to activate the calf musculovenous pump to increase venousemptying, but also to alter the patterns of blood flow in a patient. Inparticular, diastolic flow reversal in the artery may be reduced or evenprevented. This is thought to be a consequence of a reduction inperipheral vascular resistance. While enhancing blood flow waspreviously known, the finding that blood flow may be significantlyaltered is unexpected, and offers several novel ways in which the devicemay be used.

According to a first aspect of the present invention, there is provideda method of reducing peripheral vascular resistance in a leg of apatient, the method comprising administering one or more electricalstimuli to a plurality of leg muscles sufficient to cause isometriccontraction of the muscles. Also provided is a method of reducing orpreventing diastolic flow reversal in an artery in a leg of a patient,the method comprising administering one or more electrical stimuli to aplurality of leg muscles sufficient to cause isometric contraction ofthe muscles.

The reduction of peripheral vascular resistance, and the reduction ofdiastolic flow reversal, allow for the treatment of additionalconditions which were not previously known to be treatable by electricalstimulation of muscles. In particular, the invention also provides amethod for treatment of disorders characterised by increased peripheralvascular resistance. Such disorders include lower limb arterial, disease(peripheral arterial disease); impaired lower limb lymphatic drainage;cardiac diseases; restless leg syndrome (Wittmaack-Ekbom's syndrome);soft tissue injury of the lower limb (including skin and muscle bruisingand micro tears; and sports injuries); and inflammation. The inventionprovides methods for treatment of each of these disorders. The reductionof peripheral vascular resistance is also thought to be of benefit insports training and rehabilitation, whether or not the subject has aninjury.

For example, the methods of the invention may be used to reduce recoverytime after a sports event. After such an event, for example, a footballmatch, or an athletics race, even if a participant is not injured, theirperformance may take several days to recover to the pre-event level. Webelieve that the method of the invention may be of benefit in reducingthis recovery time; for example, if applied from 2-24 hours after anevent, or between training sessions.

The method may also be of benefit in other conditions in which bloodpooling may be a problem. In particular, for prevention or avoidance ofG-LOC (g-force induced loss of consciousness). In such an embodiment,the method may also comprise the steps of monitoring g-force experiencedby a subject, and adjusting the stimuli in response to variations in themonitored g-force (for example, an increased g-force may result in anincreased frequency of stimulation). Other applications includemaintaining blood flow in reduced gravity, for example, during spacetravel; reducing the likelihood of blood pooling during prolongedperiods of standing (for example, among soldiers on parade); or reducingor avoiding blackouts experienced on sudden standing.

The leg muscles are preferably the calf muscle, although in certainembodiments of the invention, stimulation of the ankle and/or footmusculature may instead or in addition be used. The leg muscles arepreferably involved in a musculovenous pump; for example, the calf,foot, and/or thigh pumps.

The stimuli may be applied directly to the muscles, or indirectly viastimulation of a suitable nerve. For example, a favoured approach is toindirectly stimulate the lower limb musculature by accessing nervegroups in the area of the popliteal fossa, where the nerve groups are ingeneral easily accessible in individuals, regardless of body mass, andwith minimum energy requirement. Unless otherwise specified, it will beappreciated that all reference herein to stimulation of a muscle isintended to encompass both direct stimulation and indirect stimulation.

A possibly undesirable effect of isolated contraction of the calfmuscles is the plantar-flexion of the foot. In a seated individual thismay cause the knee to rise, so making the process more obtrusive.Isometric contraction ensures that opposing muscles or groups of musclesare, stimulated such that there is no or little movement of the limb asa result. The stimulus may be applied directly to posterior calfmuscles; conveniently the soleus and/or gastrocnemius muscles. Indirectstimulation of the lower limb muscles may be achieved by electricalstimulation of the lateral popliteal nerve in the region of thepopliteal fosse. Specifically at the inner margin of the biceps femorismuscle, behind the fibula at the inner side of the tendon of the bicepsfemoris. Additionally, indirect stimulation of the lower limb musclesmay be further achieved by electrical stimulation of the medialpopliteal nerve, which is located medially from the lateral poplitealnerve in the region of the popliteal fosse.

A second stimulus may be applied to shin muscles; conveniently thetibialis anterior. Preferably the second stimulus is appliedsimultaneously to the stimulus applied to the calf muscles. Stimulation,of the tibial muscle alone will promote blood flow to some extent,although the primary purpose of this second stimulation is to preventunwanted limb movement. Application of a stimulus only to a posteriorcalf muscle may have the unwanted side effect of causing movement of theankle joint. Application of a stimulus to the shin muscle willcounteract any movement of the ankle joint caused by contraction of thecalf muscle, so keeping the ankle and knee joints relatively still.

Alternatively, stimulation of, the lateral popliteal nerve, in theregion of the popliteal fossa, has the advantage of initiating thecontraction of both posterior and anterior lower limb muscle groups froma single stimulation point. Such simultaneous stimulation results inisometric contraction; hence the ankle and knee joints would not betypically mobilised. Stimulation of the lateral popliteal also elicitscontraction of the foot muscles and hence, the so-called “foot-pump”.Additionally, the surprising advantage of selective stimulation of thelateral popliteal nerve is that the resultant muscular contractions areentirely compatible withstanding and walking. An additional benefit ofthis mode of indirect stimulation is the involvement of the muscles inthe sole of the foot which have been shown to contributed substantiallyto clearance of blood from the lower leg. It has further been identifiedthat stimulation of the nerve in this way, rather than the musclesdirectly, allows the method to be operated so as to engender little orno noticeable skin sensation or discomfort when used to stimulate musclecontraction:

In a clinical environment, where standing and walking are not apre-requisite, the medial popliteal nerve may be stimulated, either inisolation or in combination with stimulation of the lateral poplitealnerve. A preferred version of dual medial and lateral popliteal nervestimulation may result in near maximal contraction of the entire lowerlimb musculature, leading to enhanced efficiency and activity of boththe calf and foot venous pumps, and by extension, movement of venousblood out of the lower limb, centrally towards the abdomen.

The method preferably comprises repeatedly administering an electricalstimulus to the muscles.

A typical electrical stimulus may be at a current of between 0 to 100mA, preferably 0 to 50 mA, more preferably 1 to 40 mA, and mostpreferably between 1 to 20 mA. Other examples of stimulus currentsinclude between 15 and 30 mA.

The stimulus may be an AC waveform, although it is preferably a DCwaveform, more preferably a pulsed DC waveform. The stimulus may have afrequency of 0.01 to 100 Hz, preferably 0.1 to 80 Hz, more preferably0.1 to 50 Hz; and more preferably still 0.1 to 5 Hz. The most preferredfrequencies are 0.5-5 Hz, 1-5 Hz, preferably 1-3 Hz; for example, 1, 2or 3 Hz. In other embodiments, the frequency may be from 30 to 60 Hz,and more preferably 40 to 50 Hz. Alternatively, a stimulus with afrequency from 0.1 to 1 Hz, or from 0.33 to 1 Hz may be used. Theprecise desired frequency may depend on the purpose of the method, thedesired physiological mode of action it is intended to cause, and thegeneral physical condition, age, sex, and weight of the patient, amongother factors.

Specific examples of preferred stimuli include 20 mA, at a frequency of5 Hz, 30 mA at 3 Hz, and 28 mA at 1 Hz. Other stimuli may of course beused.

The stimulus may be applied for a duration between 0 and 1000 ms,between 100 and 900 ms, between 250 and 750 ms, between 350 and 650 ms,or between 450 and 550 ms. In certain embodiments, the stimulus may beapplied for up to 5000 ms, up to 4000 ms, up to 3000 ms, or up to 2000ms. Other durations may be used; again this may depend on the details ofthe patient or the mode of action intended. Other preferred durationsinclude from 70 to 600 ms. In certain embodiments, yet shorter durationsmay be used, for example from 25 μs to 800 μs.

Characteristics of the stimulus may vary over time. For example, asingle stimulus may increase in current over the duration of thestimulus. Preferably the increase is gradual up to a peak; the stimulusmay then either be maintained at the peak; terminate at the peak; ordegrease in a gradual manner. Alternatively, where repeated stimuli areapplied, characteristics of the stimuli may vary between differentstimuli. For example, successive stimuli may be applied at increasinglevels of current. Again, these successive stimuli may increase up to apeak gradually, followed by maintenance at that peak, or decrease fromthe peak. A cycle of increasing stimuli may be repeated a number oftimes. In preferred embodiments, each stimulus is a single pulse, ratherthan multiple brief pulses.

Stimuli may be applied at a plurality of locations on the muscles. Forexample, stimuli may be applied along the main (long) axis of the leg.Such stimuli may be applied simultaneously, or preferably sequentiallysuch that a ‘wave’ of stimuli proceeds along the leg. Preferably, such awave proceeds upward toward the body of the patient. This wave effectserves to generate a corresponding wave of muscle contraction which wavemay help to promote blood flow away from the leg. However, in preferredembodiments of the invention a stimulus is applied at a single point onthe leg, to stimulate the lateral popliteal fossa nerve, as describedabove. “A single point” may include stimulation by more than oneelectrode, for example, a pair of positive and negative electrodes, witha sufficiently small separation (for example, 1-3 cm, or up to 2 cm)such that the stimulation is experienced at a point by the user ratherthan over a larger area.

Also provided is a method for diagnosing conditions characterised byincreased peripheral, vascular resistance, the method comprisingadministering one or more electrical stimuli at a first frequency and/orcurrent to a plurality of leg muscles sufficient to cause isometriccontraction of the muscles; and monitoring blood flow in the leg todetermine whether diastolic reversal of arterial flow is reduced orprevented and/or peripheral vascular resistance is reduced.

The method may further comprise repeating the stimulation and monitoringsteps at a second frequency and/or current, and determining the level offrequency and/or current required to effect reduction or prevention ofdiastolic reversal of arterial flow; and/or reduction of peripheralvascular resistance. The level at which this occurs may give someinformation as to the severity of the condition.

The method may further comprise comparing the level of frequency and/orcurrent required to effect reduction or prevention of diastolic reversalof arterial flow and/or reduction of peripheral vascular resistance withthe levels required in a healthy control patient. Again, this may helpdiagnose a condition or give some indication as to the severity of thecondition. The healthy control patient may be selected so as to beotherwise comparable to the patient.

Also provided according, to the present invention is a method forpromoting circulation in a patient having a heart condition, the methodcomprising administering one or more electrical stimuli to a pluralityof leg muscles sufficient to cause isometric contraction of the muscles.As noted above, electrical stimulation of the musculovenous pumppromotes altered blood flow patterns, which may be beneficial inpatients having heart conditions. The heart condition may includecardiac arrest, suspected cardiac arrest, arrhythmia, brachycardia, orangina. The method may also be used as an adjunct to defibrillation inthe case of cardiac arrest. Also provided is a device for use inpromoting circulation in a patient having a heart condition, the devicecomprising at least one electrode for administering an electricalstimulus to opposed leg muscles of a patient; a power supply connectableto the electrode; and a control means for activating the electrode toadminister an electrical stimulus to the muscles sufficient to cause themuscles to contract isometrically. The invention also provides a kitcomprising such a device in combination with a defibrillator.Alternatively, the device may include a defibrillator.

Further aspects of the present invention relate to the modification ofcortical blood flow in bone. As noted in WO2006/054118, the method ofisometric muscle stimulation has been shown to promote cortical bloodflow. We have since discovered, and demonstrate herein, that boneoxygenation and bone perfusion are increased by use of the method. Thisallows more effective delivery of pharmaceutical agents to the bone,particularly those intended for treatment of bone disorders includingosteoporosis. Thus, according to a further aspect of the presentinvention there is provided a method for improving administration ofmedicaments for treatment of bone disorders, the method comprisingadministering said medicament to a patient, and administering one ormore electrical stimuli to a plurality of leg muscles sufficient tocause isometric contraction of the muscles and enhance bone perfusion.The bone disorder may be osteoporosis. Also provided is a kit fortreatment of bone disorders, the kit comprising a medicament fortreatment of a bone disorder and a device comprising at least oneelectrode for administering an electrical stimulus to opposed legmuscles of a patient; a power supply connectable to the electrode; and acontrol means for activating the electrode to administer an electricalstimulus to the muscles sufficient to cause the muscles to contractisometrically.

Improved perfusion may also be useful for improving delivery of contrastagents (for example for medical imaging purposes) to tissues such, asthe bones, tendons, ligaments, etc. An aspect of the invention thereforeprovides a method for improving delivery of contrast agents, the methodcomprising administering said contrast agent to a patient, andadministering one or more electrical stimuli to a plurality of legmuscles sufficient to cause isometric contraction of the muscles andenhance perfusion of said agent.

A still further aspect of the invention relates to cosmetic therapy. Asdemonstrated herein, use of the method increases peripheral bloodcirculation, in particular circulation in the skin. The method alsoincreases skin temperature where circulation is increased. These effectsmay be of benefit in the cosmetic treatment of individuals. For example,the effects may include reduction of cellulite or collagen deposits,improvement of skin tone, or improvement of skin condition. Thus, theinvention provides a method for cosmetic treatment of a patient, themethod comprising administering an electrical stimulus ‘to at least oneleg muscle of a patient sufficient to cause the muscles to contract’isometrically. The cosmetic treatment may be selected from reduction ofcellulite or collagen deposits, improvement of skin tone, or improvementof skin condition. Also provided is a kit for beauty therapy, the kitcomprising a device comprising at least one electrode for administeringan electrical stimulus to opposed leg muscles of a patient; a powersupply connectable to the electrode; and a control means for activatingthe electrode to administer an electrical stimulus to the musclessufficient to cause the muscles to contract isometrically.

The device described in WO2006/664118 includes certain electrodeconfigurations which may be used. We demonstrate herein data showingspecific novel electrode configurations which are perceived as morecomfortable by users. The present invention therefore provides a devicecomprising positive and negative electrodes for administering anelectrical stimulus to opposed leg muscles of a patent; a power supplyconnectable to the electrode; and a control means for activating theelectrodes to administer an electrical stimulus to the musclessufficient to cause the muscles to contract isometrically, wherein oneelectrode substantially encloses the other.

By “Substantially encloses” is meant that one electrode surrounds atleast 66%, preferably at least 75%, more preferably at least 85%, morepreferably at least 90%, and most preferably 100% of the perimeter ofthe other. It is not essential that the one electrode be entirelyenclosed by the other, although it is preferred.

It has been determined that this arrangement of electrodes leads toimproved perception of user comfort.

Preferably the positive electrode substantially encloses the negativeelectrode.

In some embodiments the electrodes are in the form of concentric, orsubstantially concentric, circles. In others, the electrodes aregenerally elongate, preferably generally quadrilateral, such asrectangular, or C-shaped or U-shaped.

Preferably one electrode has a larger area than the other electrode;preferably the larger electrode is the positive electrode.

Preferably the control means is configured to administer an ACelectrical stimulus. Preferably the waveform of the current isasymmetric; conveniently the waveform provides an initial (positive)pulse of large magnitude and short duration, followed by a (negative)pulse of small magnitude and long duration. The area under the curve ofthe two pulses will be equal. In one embodiment, the initial pulse is ofa generally square waveform.

A further aspect of the present invention provides a device comprisingpositive and negative electrodes for administering an electricalstimulus to a nerve innervating opposed leg muscles of a patient, so asto cause isometric contraction of the muscles; a power supplyconnectable to the electrodes; and control means for activating theelectrodes.

Preferably the positive and negative electrodes are separated by 20-30mm: we have found that this provides a preferred degree of stimulation.

The electrodes may be of different sizes; preferably the positiveelectrode is larger than the negative. This provides a higher chargedensity at the motor point, and greater capacitance overall. Theelectrodes may be silver electrodes. The electrodes may be continuous,or may include holes—for example, the electrodes may be solidelectrodes, or may be in the form of a mesh.

In preferred embodiments, the device comprises a flexible substrate onwhich are mounted the electrodes, the power supply, and the controlmeans. The control means may be, for example, a PCB configured toactivate the electrodes as appropriate. The power supply may be anelectrical cell. The substrate is preferably flexible, but notstretchable—this reduces the risk of the electrodes cracking orbreaking. For example, the substrate may be a thermoplastic elastomer.

The electrodes may be directly printed onto the substrate, byconventional printing means (for example pad or tampo printing).Similarly, conductive tracks may also be printed onto the substrate ifdesired.

The substrate may be in the form of an elongate strip or tongue, withthe electrodes spaced along the strip. Such an arrangement may require aconductive track to be placed from the power supply, to the furtherelectrode, passing close to the nearer electrode. In such, arrangements,the device may further comprise one or more insulative strips or regionsarranged to separate the conductive track from the nearer electrode;insulative strips may, also or instead be arranged along the edges ofthe strip to prevent current leaking outside the area of the strip.Alternatively, or in addition, the substrate may comprise a recessedgroove within which a conductive track may be located; thereby servingto separate the track from the electrode.

In certain embodiments, the device may be configured to be implantablein a patient, for example, implantable subcutaneously. This would be ofbenefit in chronic indications where long term use of the device isrequired.

The device further comprises a conductive gel overlying the electrodes.The gel is preferably in a single piece overlying both electrodes, forease of manufacture as well as structural integrity. We have determinedthat a single piece of gel may be used, based on the bulk resistivity ofthe material and geometry, so that leakage resistance is much greaterthan delivery resistance. Examples of gels which may be used includehydrogel or silicone.

The device may be assembled as follows. The flexible substrate may beproduced as a generally flat elongate strip and a recess forming acompartment. The electrodes and conductive tracks are then printed ontothe substrate, and the power supply and control means placed into therecess. This serves to connect all the electrical connections. Therecess may then be closed, for example, by sonic welding a cover to sealthe power supply and control means into the recess. Finally a gel isplaced over the electrode s.

The device may further comprise a locating mark to aid correct placementin use.

The device may include a press button for activating or deactivating thedevice. The control means may be configured to provide a plurality ofactivation modes (for example, with different stimulationcharacteristics); the press button may be used to cycle through thesemodes. The device may include a display means, such as a light or anLED, to indicate the selected activation mode.

Preferably the device is for reducing diastolic flow reversal.

In certain embodiments the device may be disposable; for example, aftera single use.

The device is intended to be sufficiently small and light—for example,less than 10 cm in length, and weighing less than 100 g, preferably lessthan 20 g—so as to be highly portable.

In use the device may be operated so as to engender little or nonoticeable skin sensation or discomfort when activated to stimulatemuscle contraction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A through 1C show the measurements of arterial blood flow in afirst subject at levels of stimulation of 20 mA, 5 Hz (FIG. 1A); 5 mA, 5Hz (FIG. 1B); and at no stimulation (FIG. 1C).

FIGS. 2A through 2C show the measurements of arterial blood flow in asecond subject at a level of stimulation of 20 mA, 3 Hz (FIG. 2A);immediately after stimulation (FIG. 2B); and at rest (FIG. 2C).

FIGS. 3A through 3F show the measurements of arterial blood flow in athird subject at levels of stimulation of 10 mA, 3 Hz (FIG. 3A); 1 mA, 3Hz (FIG. 3B); 20 mA, 5 Hz (FIG. 3C); 5 mA, 1 Hz (FIG. 3D); 5 mA, 3 Hz(FIG. 3E); and at rest (FIG. 3F).

FIG. 4 compares the speed of skin blood flow in stimulated andunstimulated limbs at different levels of stimulation.

FIG. 5 compares skin temperature in stimulated and unstimulated limbs atdifferent levels of stimulation.

FIG. 6 shows oxyhemoglobin levels measured by infrared spectroscopy inthe tibia during stimulation cycles.

FIG. 7 shows the change in deoxyhemoglobin levels in all patients duringstimulation.

FIG. 8 shows a first desired electrode arrangement.

FIG. 9 shows a second desired electrode arrangement.

FIG. 10 shows several electrode arrangements tested.

FIG. 11 shows asymmetric and symmetric waveforms tested.

FIGS. 12 and 13 show results from electrode and waveform comforttesting.

FIGS. 14 to 17 show views of an embodiment of a device according to thepresent invention.

DETAILED DESCRIPTION OF THE DRAWINGS

A device for electrically stimulating leg muscles is described in detailin WO2006/054118, and the reader is referred to that publication for afull description “of the device. The present invention is primarilybased on a number of unexpected effects observed from use of that andsimilar devices, although we also describe a particularly preferredembodiment of the device.

In brief, though, one embodiment of the device as described inWO2006/054118 includes a loop of elasticated material which, in use, maybe worn around a user's lower limb. On the interior surface of theelasticated material are disposed first and second electrodes connectedby conductive wires to a cradle which is integral with the elasticatedmaterial.

Mounted within the cradle is a control module, which includes a, powercell, a control processor, and an external LED.

The control module is removable from the cradle, with a pair of detentsand corresponding recesses allowing the cradle and control module tointerlock. The control module and cradle carry, corresponding electricalcontact surfaces which provide for electrical communication between thecontrol module and the first and second electrodes via the conductivewires,

The control processor includes a timer module, a data store, a programstore, and a logic unit.

In use, the device is operated as follows. The elasticated loop is wornon a user's lower limb, such that the first electrode is in contact withthe calf muscle at the rear of the limb, and the second electrode is incontact with the anterior muscle of the limb. When the control module isengaged with the cradle, the device is automatically activated.

The program store is preloaded with an operating program arranged toactivate the electrodes each minute using a 40 Hz pulsed DC of 20 mA for0.1 second. Both electrodes are activated simultaneously. The timermodule serves to generate appropriate timing signals, while the logicunit executes the program of the program store.

As the electrodes are activated, the user's muscles are stimulated tocontract. Contraction of the rear calf muscle, caused by the firstelectrode, serves to pump blood out of the leg using the calf pumpthereby reducing pooling of the blood. Contraction of the anteriormuscle, caused by the second electrode, is intended to reduce unwantedmovement of the ankle by counterbalancing the contraction of the rearcalf muscle. Simultaneously with each activation, of the electrodes, theLED on the outer surface of the control module is also activated; thisprovides a visual confirmation that the device is operating.

The foregoing is a description of one embodiment of the device. However,a suitable device for stimulating muscles may be assembled fromconventional skin, electrodes and a suitable electrical power supply. Itis this form of test rig which was used in the following experiments.

Experimental Design

Study Title: A study to determine the effects of a novel method forenhancing lower limb blood flow in Healthy Adult Volunteers.

Objectives: The primary objective of this study was to evaluate theeffectiveness of topical electrical stimulation in enhancing lower limbperfusion. The secondary objective was to evaluate with duplexultrasound and plethysmography techniques the blood flow velocity andvolume changes associated with varying the intensity and level ofelectrical stimulation.

Study Design: One-centre, physiological response study in healthyVolunteers.

Stimulus Application: The effects of electrical stimulation on lowerlimb blood flow were investigated in healthy volunteers during a 4-hourperiod of prolonged sitting. Each subject completed his or her study satin an Industry Standard airline seat. The stimulator used customstimulation protocols. Superficial electrical stimulation was applied tothe lateral popliteal nerve located in the area of the popliteal fossa.

Sample Size: 30 Volunteers

Environmental Conditions

The examinations were carried out in a quiet, stable, draught freeenvironment, both temperature and humidity controlled (24±10 C, relativehumidity 30-40%). Volunteers were instructed to have a light breakfast,avoiding fatty foods, tobacco and caffeine and to abstain from vigorousexercise from the previous evening onwards. The volunteers were lightlyclad (in shorts), sat in a comfortable position with legs bent at theknees.

The effects of electrical stimulation on lower limb blood flow wereinvestigated in healthy Volunteers during a 4-hour period of prolongedsitting. Each subject completed his or her study sat in an IndustryStandard airline seat, which has been specifically obtained for thisinvestigation.

The leg clearance distance was be set at 34 inches, by positioning of atoe-bar. Each subject was positioned in the seat by a safety belt tomaintain a close uniformity of posture and actively encouraged to remainas passive as can be tolerated by the individual.

Physiological Assessments

During this phase, the amplitude and frequency of the electricalstimulation was varied and associated changes in blood flow recorded.

Changes in lower limb blood flow were evaluated using routinenon-invasive plethysmographic techniques (photoplethysmography, straingauge plethysmography and air plethysmography), transcutaneous oxygenand where possible, colour flow duplex ultrasound.

Changes in blood flow and volume in response to the protocols werecompared to blood flow and velocity changes determined by voluntarymuscle action i.e. Volunteers were be asked to perform 10 plantarflexions (10 toe lifting movements—with the heel on the ground). This isthe maximum physiological response that can be obtained in the sittingposition.

Volunteers were asked to evaluate acceptance and tolerability ofelectrical stimulation sequences by use of a questionnaire (VerbalRating Scores) and a scoring index (Visual Analogue Scores). Discomfortwas related to normal measurement of blood pressure, measured on theupper arm using a standard sphygmomanometer cuff.

Following the period of sitting for 4-hours Volunteers will bere-examined with duplex ultrasound to recheck the status of the deepveins to exclude the development of significant thrombi. The study wasperformed on each subject at two separate occasions which were thenaveraged to reduce experimental bias.

Stimulator

The device produced a range of pre-Set programmed corresponding todifferent stimulation currents, and pulse frequencies. The waveform wasspecifically designed for motor nerve stimulation, as opposed to directmuscle stimulation. Pulse amplitudes ranged from 1 mA to 40 mA, withfrequencies ranged from 1 Hz to 5 Hz, which is a significant departurefrom the Physiotherapy and TENS protocols (which generally applysubstantively higher currents and frequencies).

We applied a succession of 15 different stimulation programmes to eachsubject during the course of each study, according to a 2-dimensionalmatrix of amplitude and frequency, as shown in Table 1. The duration ofeach stimulation programme was 5 minutes, and will be followed by a10-minute recovery phase to allow vascular re-equilibration prior to thenext sequence.

TABLE 1 Stimulation sequence Programme # Amplitude/mA Frequency/Hz 1 1 12 1 3 3 1 5 4 5 1 5 5 3 6 5 5 7 10 1 8 10 3 9 10 5 10 20 1 11 20 3 12 205 13 40 1 14 40 3 15 40 5

During each of the 15 programmes, non-invasive blood flow and volumeparameters were measured as specified above, with reference to thelevels observed during voluntary muscle contraction, and with referenceto levels observed in the contralateral limb.

Example 1: Blood Flow Patterns

The patterns of venous blood flow in volunteers were monitored usingvascular ultrasound of the stimulated leg. Representative examples areshown in FIGS. 1-3, FIG. 1a shows stimulation in a first subject at 20mA, 5 Hz; FIG. 1b at 5 mA, 5 Hz; and FIG. 1e with no stimulation. FIG.2a shows a second, subject stimulated at 20 mA, 3 Hz; FIG. 2b the samesubject immediately after stimulation; and FIG. 2c the subject at rest.FIG. 3a shows a third subject undergoing stimulation at 10 mA, 3 Hz;FIG. 3b at 1 mA, 3 Hz; FIG. 3c at 20 mA, 5 Hz; FIG. 3d at 5 mA, 1 Hz;FIG. 3 e at 5 mA, 3 Hz; and FIG. 3f the subject at rest.

In these examples there was a four-fold increase in venous blood flowvelocity from baseline. There was also a significant increase infrequency of cephalad (toward the head) venous blood flow withapplication of the stimulus.

Flow velocity in the superficial femoral artery doubles and, the reverseflow components of the pulse wave arterial flow waveform are completelyabolished with application of the stimulus.

Reverse flow in the superficial femoral artery is due to high resistanceof the peripheral vessels; therefore forward flow throughout the cardiaccycle suggests a significant reduction in peripheral vascularresistance.

A fall in total peripheral resistance (consequent of the increase invascular pump activation by the device) may be illustrated by the laserDoppler and vascular venous vessel ultrasound blood flow increases. Theconsequence of this is that cardiac output tends to increase. We havealso shown that there is no significant increase in the heart rate(beats per minute). This may be demonstrated by the increase in thearterial blood flow and the change in the waveform.

Importantly the increases in blood flow in the various tissues in theleg are proportionate, and therefore there is an increase in blood flowin all of the tissues; hence no ‘steal’ of blood from any adjacenttissue. All tissues, skin, muscle, bone etc have increased perfusion ofblood.

Resistance of blood flow can influence arterial pressure, cardiacoutput, distribution of cardiac output to systemic organs, distributionof organ blood flow to the various organ tissues, partitioning of tissueblood flow between capillaries and arteriovenous anastomoses, capillaryhydrostatic pressure, and the distribution of blood flow within thecardiovascular system. All of which, are, upregulated by the device atcertain, defined settings.

A parallel is in exercise, where the total peripheral resistance alsodecreases as work load, measure by oxygen consumption increases. Thefall in vascular resistance is accompanies by a progressive increase incardiac output. The device mimics this event without a substantiveincrease in workload and hence minimal oxygen consumption compared toexercise.

Increases in microcirculatory blood flow may additionally be explainedby an increased utilisation of previously closed or ‘resting’ capillarynetworks, which become available for local exchange. The effect of thisis a greatly increased tissue perfusion and a further effect onperipheral vascular resistance.

This is a novel and unique observation, which has significant impact onthe cardiovascular system and vascular therapeutics.

Thus, application of the electrical stimulus can increase venous bloodflow, and can reduce or prevent diastolic flow reversal in the artery.Note that this does not occur at all settings; FIG. 3d shows no flowreversal when stimulated at 5 mA, 1 Hz.

This effect has the potential for a wide range of therapeutic anddiagnostic applications. For example, as the effect only occurs atcertain settings, it is likely that the current and frequency at whichit appears in individual patients may be characteristic of their normalarterial flow and/or peripheral vascular resistance. This may be used todiagnose the presence and/or severity of circulatory disorders in apatient. Therapeutically, the modified arterial flow and reducedperipheral vascular resistance may be of benefit in treatment of a rangeof conditions, including ischaemia, cardiac vessel disease, ulceration,and so on.

Example 2

Laser Doppler Fluxmetry (LDF) was used to measure the speed of skinblood flow; the results are shown in FIG. 4. LDF flux (speed of blood)is increased up to ˜1000% in stimulated leg compared to baseline and theunstimulated leg, which showed values only around baseline level.

Example 3

Skin temperature was measured in stimulated and unstimulated legs; theresults are shown in FIG. 5. There is a slight increase in temperatureat all stimulations in the stimulated leg compared to unstimulated leg.Temperature in the body is generated by metabolism and blood flow. Asthe metabolism is not altered during the stimulations the slightincrease in skin temperature is an indicator for increased blood flow insuperficial layers of the skin.

Example 4

Therapy for Osteoporosis

Every year there are approximately 2 million osteoporotic fracturesworldwide. (in 1990 there were 1.66 million, and 6 million per yearforecast by 2050 according to World Health Organisation). High-riskgroups include the elderly population, and people with spinal cordinjuries.

In the healthy individual, bone is constantly being remodeled accordingto physical requirements. Osteoclast cells remove minerals from bone,allowing collagen matrix to resorb, while osteoblasts lay down newcollagen matrix and mineral deposits.

Various theoretical models have been proposed over the last century forthe mechanism by which the body controls bone density. Wolff, in 1892,proposed that bone deposits followed the patterns of stress in the bone.Frost's 1987 “mechanostat” theory suggested that bone was maintained tomaintain uniform strain under habitual loads.

Models for explaining why some individuals developed problems withmaintaining bone density initially focused on disuse. In the ageingindividual, decreasing use of the bone leads to lower doses of thestresses and strains required to signal bone maintenance. More recently,however, it has been suggested that there is a vascular component to theetiology. Osteoporosis appears to occur in individuals with impairedbone perfusion, either by reduced angiogenesis (itself aggravated bydisuse), atherosclerosis restricting flow in existing vessels, or simplylower activity levels causing less blood circulation. (Trueta J. Therole of the vessels in osteogenesis. J Bone Joint Surg Br. 1993).

The present invention has the potential to mitigate vascular riskfactors for osteoporosis, by increasing perfusion of bone. This can helpin two ways. Firstly, augmenting blood supply overcomes limitation ofbone modelling caused by reduced perfusion. Secondly, pharmaceuticalinterventions for osteoporosis can be delivered more effectively to thebone by improving bone perfusion.

A study carried put under the supervision of the inventors hasdemonstrated that 1) Blood flow in the tibia and femur are enhanced whenthe device is active; and 2) Perfusion indices indicate that the bone isless hypoxic when the device is active.

FIG. 6 shows Oxyhaemoglobin level measured by infrared spectroscopy inthe tibia, during stimulation cycles (100 seconds on, 100 seconds off).Total blood content (top line) drops during stimulation, indicating thatthe calf pump aids evacuation, and that oxyhaemoglobin levels, riseduring stimulation, indicating better oxygenation (reduced hypoxia).

FIG. 7 shows the results for 12 subjects summated, showing the mean andstandard deviation reduction of deoxyhaemoglobin relative to baseline.The device (labelled NMS) on the chart shows a significant reductionwhen active. As an idea of scale, this is compared with the reductionachieved by augmenting blood supply using the tilt-table method. This isa known hydrostatic step-change, which consists of the subject lyingsupine on a tilt table, and while strapped to the table they are tiltedinto a standing upright position, providing a very large hydrostaticvascular stimulus. This chart may be considered analogous to comparingDVT parameters with the device to foot flexion.

The foregoing examples indicate that the device and method may be usedto address new clinical targets. These include:

-   -   Lower limb arterial disease—Peripheral Arterial Disease    -   Enhanced lower limb lymphatic drainage.    -   Cardiac diseases    -   Fractures    -   Enhancement of bone marrow perfusion—for example the management        of sickle cell crises, ischaemic bone marrow, stem cell and bone        marrow harvest procedures—as well as improving treatment of        cancers by delivering drugs to the bone Marrow.    -   Soft tissue injury of the lower limb—skin and muscle bruising        and micro tears.    -   Sports training and rehabilitation.    -   Restless Leg Syndrome (Wittmaack-Ekbom's syndrome)    -   Enhancement of endothelial-derived nitric oxide and prostacyclin        release.

Example 5

Discomfort

Neuromuscular stimulation is commonly used to elicit muscle activity forseveral different applications. These include exercise, rehabilitationand restoration of function (eg drop foot stimulator) and more recentlyaugmentation of blood supply using the soleus pump for various purposes,

NMS has commonly been used previously for restoration of function ininsensate individuals, eg with spinal cord injury. In these users,discomfort or pain associated with the stimulation is not an issue.

In the sensate user, however, discomfort or pain during stimulation isan issue, and sometimes a limiting factor in the level of stimulationapplied.

In NMS, an electrical stimulus is used to cause contraction of a systemof skeletal muscles. Unfortunately, efferent (motor) and afferent(sensory) nerves are typically bundled together in the same nerveconduit, and additional sensory nerves are present in the skin. Thismeans that, as well as stimulating motor nerves, NMS causes somestimulation of sensory nerves. If sensation signals arrive at the brain,in large numbers and rapid succession, they may be perceived as pain insome individuals.

Relationships have been found between electrode size and stimulatoryresponse. It has also been found that stimulation quality and toleranceare sensitive to electrode position. These relationships have now beeninvestigated further by the inventors, in a series of experiments.

One hypothesis tested was that smaller electrodes would be bettertolerated, since they allow us to target accurately the region of theperoneal lateral popliteal, without unnecessary stimulation ofsurrounding areas of skin receptors. This was not found to be reliablythe case in our experiments. This finding may be rationalised asfollows.

Current density is usually maximal at the skin/electrode interface,whereas the quality of muscle contraction is determined by the currentdensity at the point of excitation.

For a given current, a smaller electrode provides increased currentdensity at the skin. However, this does not necessarily translate tomaximal current density at the point of excitation. The electrodes arenecessarily spaced from each other to avoid short circuit Charge flowsthrough the tissues from one electrode to the other electrode in aplurality of indirect routes. Therefore the charge takes a wider path inthe tissue than at the interface between electrode and skin, with theeffect that the charge density is at its highest in the skin, and lowerwithin the tissue, and at the excitation point of the nerve.

Experiments were conducted with various arrangements of electrodes toallow smaller differentials between current density at the skininterface and at the desired stimulation point.

It has been found advantageous to have two electrodes of different size.Since excitation of the nerve is achieved by depolarising the nerve(which normally has a positive extracellular charge and a negativeintracellular charge) it is the negative electrode (cathode) that causesthe nerve to achieve action potential. It is found to be advantageous toposition a small cathode in the precise region to be stimulated, and alarger anode at a site somewhat, removed, allowing high current densityat the stimulation site only, and low current density (below actionpotential) generally.

A refinement to this technique is to provide anodes either side of thecathode, giving a much wider spread of (accordingly lower) chargedensity at the anodes. Two possible embodiments of electrodes includethree parallel strips (centre negative)—see FIG. 8—and target(bull's-eye negative)—see. FIG. 9. The target variant may have a closedor open outer circle, and, may be oval.

The electrode structures were tested experimentally.

Ten normal healthy subjects were used, ranging in age between 24 and 50.A Visual Analog Score was measured by asking each subject to draw a markon a standard 10 cm line segment, representing where their sensation wason a scale from no discomfort (far left) to extreme pain (far right). Asystem was adopted for normalising these scores relative to a standardsensation, which was taken to be the existing electrode configurationand waveform used in the previous studies.

A normalised discomfort score was then derived for each configurationbased on the horizontal distance between the VAS for this configurationand the VAS for the standard configuration. Thus, a positive score willindicate less comfortable, and a negative score will indicate morecomfortable,

FIG. 10 (A-F) describes the electrode configurations used.

Two waveforms were used, symmetric and asymmetric (see FIG. 11). In bothcases, the overall charge is balanced (area A is equal), so no galvanicirritation is possible.

Table 2 gives the key to the electrode/waveform combinations used.

TABLE 2 Electrode Config configuration waveform  1 A Asym  2 A Sym  3 BAsym  4 B Sym  5 C Asym  6 C Sym  7 D Asym  8 D Sym  9 E Asym 10 E Sym11 F Asym 12 F Sym

FIG. 12 shows each stimulation configuration as a number on the x axis.For each, the median normalised VAS is shown as a blue bar, with therange between first and third quartiles shown as whiskers.

It can be seen that the most preferred combinations are C, D, and to alesser extent B, all with the asymmetrical waveform.

Note that configuration 1 shows a shore of 0 in every case bydefinition.

FIG. 13 shows the Normalised VAS ratings for each subject as a separatecoloured line. This representation makes still more obvious thepreference for the asymmetrical waveform.

Optimal configuration is the symmetrical/target arrangement, negativeelectrode in the middle, and positive larger than negative. Waveformfindings indicate that asymmetrical but charge-balanced (large positivespike followed by smaller but longer duration negative current) isoptimal for comfort.

A preferred embodiment of a device according to the invention is shownin FIGS. 14 to 17. The device 10 comprises a flexible, non-stretchablethermoplastic elastomer substrate 12 which includes an elongate tongue14 at one end, and a moulded recess 16 at the other.

On the tongue 14 are printed positive 18 and negative 20 electrodes. Thepositive is slightly larger than the negative. Each electrode includes aconductive track 22, 24 leading from the electrode to a respectivecontact point 26, 28 located in the recess 16.

Not shown in the figures are an insulative strip arranged between thepositive track 22 and the negative electrode 20, and similar strips atthe edges of the tongue, to prevent unwanted leakage of current.

Within the recess 16 are placed an electrical cell (not shown), and aPCB (not shown) including suitable circuitry to control the electrodes.Together with the conductive tracks 22, 24 and contact points 26, 28,this forms a complete circuit. A plastic cover is then sonically weldedover the recess 16 to seal the components. A layer of gel is then placedover the whole device 10; this provides an electrical contact with auser's limb and helps keep the device adhered to a user. The gel may beprotected in transit by a peel able backing layer.

The outer surface of the recess 16 is formed with an integral diaphragmbutton 30 and an aperture 32 for displaying an LED. The button 30 isarranged to contact a corresponding button on the battery housing or PCBto activate the device. The aperture 32 displays an LED which indicateswhether the device is operating.

The invention claimed is:
 1. A method of reducing or preventingdiastolic flow reversal in an artery in a leg of a patient comprising:administering an electrical stimulus having a frequency of from 1 to 3Hz and a current of between 0 to 100 mA by means of a single negativesurface electrode and a single positive surface electrode to a nerveinnervating opposed leg muscles sufficient to cause isometriccontraction of the muscles, and wherein, in said method, said electricalstimulus is administered to only one nerve wherein the nerve isstimulated from a single stimulation point and wherein said singlenegative surface electrode is located at said single stimulation point,and wherein the single positive surface electrode is shaped andpositioned so as to provide the single positive surface electrode eitherside of the single negative surface electrode, thereby reducing orpreventing diastolic flow reversal in an artery in a leg of a patient.2. The method of claim 1, wherein the electrical stimulus has afrequency of 1 Hz.
 3. The method of claim 1, wherein the electricalstimulus has a current of 15-30 mA.
 4. A method of reducing orpreventing diastolic flow reversal in an artery in a leg of a patientcomprising: administering an electrical stimulus having a frequency of 1Hz and a current of between 0 to 100 mA by means of a single negativesurface electrode and a single positive surface electrode to a nerveinnervating opposed leg muscles sufficient to cause isometriccontraction of the muscles, wherein said single positive surfaceelectrode is larger than said negative single surface electrode and saidsingle positive surface electrode is shaped and positioned so as toprovide the single positive surface electrode either side of the singlenegative surface electrode, and wherein, in said method, said electricalstimulus is administered to only one nerve wherein the nerve isstimulated from a single stimulation point and wherein said singlenegative surface electrode is located at said single stimulation point,thereby reducing or preventing diastolic flow reversal in an artery in aleg of a patient.